| 词条 | Thrombin |
| 释义 |
Thrombin ({{EC number|3.4.21.5}}, fibrinogenase, thrombase, thrombofort, topical, thrombin-C, tropostasin, activated blood-coagulation factor II, blood-coagulation factor IIa, factor IIa, E thrombin, beta-thrombin, gamma-thrombin) is a serine protease, an enzyme that, in humans, is encoded by the F2 gene.[1][2] Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions. HistoryAfter the description of fibrinogen and fibrin, Alexander Schmidt hypothesised the existence of an enzyme that converts fibrinogen into fibrin in 1872.[3] PhysiologySynthesisThrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is co-translationally modified in a vitamin K-dependent reaction that converts 10-12 glutamic acids in the N terminus of the molecule to gamma-carboxyglutamic acid (Gla).[4] In the presence of calcium, the Gla residues promote the binding of prothrombin to phospholipid bilayers. Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade. In human adults, the normal blood level of antithrombin activity has been measured to be around 1.1 units/mL. Newborn levels of thrombin steadily increase after birth to reach normal adult levels, from a level of around 0.5 units/mL 1 day after birth, to a level of around 0.9 units/mL after 6 months of life.[5] Mechanism of actionIn the blood coagulation pathway, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin, and XIII to XIIIa. Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot. Thrombin interacts with thrombomodulin.[6][7]As part of its activity in the coagulation cascade, thrombin also promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet. Negative feedbackThrombin bound to thrombomodulin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity. Thrombin is also inactivated by antithrombin, a serine protease inhibitor. StructureThe molecular weight of prothrombin is approximately 72,000 Da. The catalytic domain is released from prothrombin fragment 1.2 to create the active enzyme thrombin, which has a molecular weight of 36,000 Da. Structurally, it is a member of the large PA clan of proteases. Prothrombin is composed of four domains; an N-terminal Gla domain, two kringle domains and a C-terminal trypsin-like serine protease domain. Factor Xa with factor V as a cofactor leads to cleavage of the Gla and two Kringle domains (forming together a fragment called fragment 1.2) and leave thrombin, consisting solely of the serine protease domain.[9]As is the case for all serine proteases, prothrombin is converted to active thrombin by proteolysis of an internal peptide bond, exposing a new N-terminal Ile-NH3. The historic model of activation of serine proteases involves insertion of this newly formed N-terminus of the heavy chain into the β-barrel promoting the correct conformation of the catalytic residues.[10] Contrary to crystal structures of active thrombin, hydrogen-deuterium exchange mass spectrometry studies indicate that this N-terminal Ile-NH3 does not become inserted into the β-barrel in the apo form of thrombin. However, binding of the active fragment of thrombomodulin appears to allosterically promote the active conformation of thrombin by inserting this N-terminal region.[11] GeneThe thrombin (prothrombin) gene is located on the eleventh chromosome (11p11-q12).[1] There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency,[12] which should not be confused with the prothrombin G20210A mutation, which is also called the factor II mutation. Prothrombin G20210A is congenital.[13] Prothrombin G20210A is not usually accompanied by other factor mutations (i.e., the most common is factor V Leiden). The gene may be inherited heterozygous (1 pair), or much more rarely, homozygous (2 pairs), and is not related to gender or blood type. Homozygous mutations increase the risk of thrombosis more than heterozygous mutations, but the relative increased risk is not well documented. Other potential risks for thrombosis, such as oral contraceptives may be additive. The previously reported relationship of inflammatory bowel disease (i.e., Crohn's disease or ulcerative colitis) and prothrombin G20210A or factor V Leiden mutation have been contradicted by research.[14] Role in diseaseActivation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g., hypoprothrombinemia). Anti-prothrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant also known as (antiphospholipid syndrome). Hyperprothrombinemia can be caused by the G20210A mutation. Thrombin, a potent vasoconstrictor and mitogen, is implicated as a major factor in vasospasm following subarachnoid hemorrhage. Blood from a ruptured cerebral aneurysm clots around a cerebral artery, releasing thrombin. This can induce an acute and prolonged narrowing of the blood vessel, potentially resulting in cerebral ischemia and infarction (stroke). Beyond its key role in the dynamic process of thrombus formation, thrombin has a pronounced pro-inflammatory character, which may influence the onset and progression of atherosclerosis. Acting via its specific cell membrane receptors (protease activated receptors: PAR-1, PAR-3 and PAR-4), which are abundantly expressed in all arterial vessel wall constituents, thrombin has the potential to exert pro-atherogenic actions such as inflammation, leukocyte recruitment into the atherosclerotic plaque, enhanced oxidative stress, migration and proliferation of vascular smooth muscle cells, apoptosis and angiogenesis.[15][16][17] Thrombin is implicated in the physiology of blood clots. Its presence indicates the existence of a clot. In 2013 a system for detecting the presence of thrombin was developed in mice. It combines peptide-coated iron oxide attached to "reporter chemicals". When a peptide binds to a thrombin molecule, the report is released and appears in the urine where it can be detected. Human testing has not been conducted.[18] ApplicationsResearch toolDue to its high proteolytic specificity, thrombin is a valuable biochemical tool. The thrombin cleavage site (Leu-Val-Pro-Arg-Gly-Ser) is commonly included in linker regions of recombinant fusion protein constructs. Following purification of the fusion protein, thrombin can be used to selectively cleave between the Arginine and Glycine residues of the cleavage site, effectively removing the purification tag from the protein of interest with a high degree of specificity. Medicine and surgeryProthrombin complex concentrate and fresh frozen plasma are prothrombin-rich coagulation factor preparations that can be used to correct deficiencies (usually due to medication) of prothrombin. Indications include intractable bleeding due to warfarin. Manipulation of prothrombin is central to the mode of action of most anticoagulants. Warfarin and related drugs inhibit vitamin K-dependent carboxylation of several coagulation factors, including prothrombin. Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site. Recombinant thrombin is available as a powder for reconstitution into aqueous solution. It can be applied topically during surgery, as an aid to hemostasis. It can be useful for controlling minor bleeding from capillaries and small venules, but ineffective and not indicated for massive or brisk arterial bleeding.[19][20][21] Food productionThrombin, combined with fibrinogen, is sold under the brand name Fibrimex for use as a binding agent for meat. Both proteins in Fibrimex derives from porcine or bovine blood.[22] According to the manufacturer it can be used to produce new kinds of mixed meats (for example combining beef and fish seamlessly). The manufacturer also states that it can be used to combine whole muscle meat, form and portion these thus cutting down on production costs without a loss in quality.[23] General secretary Jan Bertoft of Swedish Consumers' Association has stated that "there is danger of misleading the consumers since there is no way to tell this reconstituted meat from real meat"[22] See also
References1. ^1 {{cite journal | vauthors = Royle NJ, Irwin DM, Koschinsky ML, MacGillivray RT, Hamerton JL | title = Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively | journal = Somatic Cell and Molecular Genetics | volume = 13 | issue = 3 | pages = 285–92 | date = May 1987 | pmid = 3474786 | doi = 10.1007/BF01535211 }} 2. ^{{cite journal | vauthors = Degen SJ, Davie EW | title = Nucleotide sequence of the gene for human prothrombin | journal = Biochemistry | volume = 26 | issue = 19 | pages = 6165–77 | date = September 1987 | pmid = 2825773 | doi = 10.1021/bi00393a033 }} 3. ^{{cite journal|author=Schmidt A|year=1872|title=Neue Untersuchungen ueber die Fasserstoffesgerinnung|journal=Pflügers Archiv für die gesamte Physiologie|volume=6|pages=413–538|doi=10.1007/BF01612263}} 4. ^{{cite journal | vauthors = Knorre DG, Kudryashova NV, Godovikova TS | title = Chemical and functional aspects of posttranslational modification of proteins | journal = Acta Naturae | volume = 1 | issue = 3 | pages = 29–51 | date = October 2009 | pmid = 22649613 | pmc = 3347534 }} 5. ^{{cite journal | vauthors = Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Powers P | title = Development of the human coagulation system in the full-term infant | journal = Blood | volume = 70 | issue = 1 | pages = 165–72 | date = July 1987 | pmid = 3593964 }} 6. ^{{cite journal | vauthors = Bajzar L, Morser J, Nesheim M | title = TAFI, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex | journal = The Journal of Biological Chemistry | volume = 271 | issue = 28 | pages = 16603–8 | date = July 1996 | pmid = 8663147 | doi = 10.1074/jbc.271.28.16603 }} 7. ^{{cite journal | vauthors = Jakubowski HV, Owen WG | title = Macromolecular specificity determinants on thrombin for fibrinogen and thrombomodulin | journal = The Journal of Biological Chemistry | volume = 264 | issue = 19 | pages = 11117–21 | date = July 1989 | pmid = 2544585 | doi = }} 8. ^{{PDB|1nl2}}; {{cite journal | vauthors = Huang M, Rigby AC, Morelli X, Grant MA, Huang G, Furie B, Seaton B, Furie BC | title = Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins | journal = Nature Structural Biology | volume = 10 | issue = 9 | pages = 751–6 | date = September 2003 | pmid = 12923575 | doi = 10.1038/nsb971 }} 9. ^{{cite journal | vauthors = Davie EW, Kulman JD | title = An overview of the structure and function of thrombin | journal = Seminars in Thrombosis and Hemostasis | volume = 32 Suppl 1 | pages = 3–15 | date = April 2006 | pmid = 16673262 | doi = 10.1055/s-2006-939550 }} 10. ^{{Cite journal|last=Huber|first=Robert|last2=Bode|first2=Wolfram|date=1978-03-01|title=Structural basis of the activation and action of trypsin|journal=Accounts of Chemical Research|volume=11|issue=3|pages=114–122|doi=10.1021/ar50123a006|issn=0001-4842}} 11. ^{{cite journal | vauthors = Handley LD, Treuheit NA, Venkatesh VJ, Komives EA | title = Thrombomodulin Binding Selects the Catalytically Active Form of Thrombin | journal = Biochemistry | volume = 54 | issue = 43 | pages = 6650–8 | date = November 2015 | pmid = 26468766 | pmc = 4697735 | doi = 10.1021/acs.biochem.5b00825 }} 12. ^{{cite journal | vauthors = Degen SJ, McDowell SA, Sparks LM, Scharrer I | title = Prothrombin Frankfurt: a dysfunctional prothrombin characterized by substitution of Glu-466 by Ala | journal = Thrombosis and Haemostasis | volume = 73 | issue = 2 | pages = 203–9 | date = February 1995 | pmid = 7792730 | doi = 10.1055/s-0038-1653751}} 13. ^{{cite journal | vauthors = Varga EA, Moll S | title = Cardiology patient pages. Prothrombin 20210 mutation (factor II mutation) | journal = Circulation | volume = 110 | issue = 3 | pages = e15–8 | date = July 2004 | pmid = 15262854 | doi = 10.1161/01.CIR.0000135582.53444.87 }} 14. ^{{cite journal | vauthors = Bernstein CN, Sargent M, Vos HL, Rosendaal FR | title = Mutations in clotting factors and inflammatory bowel disease | journal = The American Journal of Gastroenterology | volume = 102 | issue = 2 | pages = 338–43 | date = February 2007 | pmid = 17156138 | doi = 10.1111/j.1572-0241.2006.00974.x }} 15. ^{{cite journal | vauthors = Borissoff JI, Spronk HM, Heeneman S, ten Cate H | title = Is thrombin a key player in the 'coagulation-atherogenesis' maze? | journal = Cardiovascular Research | volume = 82 | issue = 3 | pages = 392–403 | date = June 2009 | pmid = 19228706 | doi = 10.1093/cvr/cvp066 }} 16. ^{{cite journal | vauthors = Borissoff JI, Heeneman S, Kilinç E, Kassák P, Van Oerle R, Winckers K, Govers-Riemslag JW, Hamulyák K, Hackeng TM, Daemen MJ, ten Cate H, Spronk HM | title = Early atherosclerosis exhibits an enhanced procoagulant state | journal = Circulation | volume = 122 | issue = 8 | pages = 821–30 | date = August 2010 | pmid = 20697022 | doi = 10.1161/CIRCULATIONAHA.109.907121 }} 17. ^{{cite journal | vauthors = Borissoff JI, Spronk HM, ten Cate H | title = The hemostatic system as a modulator of atherosclerosis | journal = The New England Journal of Medicine | volume = 364 | issue = 18 | pages = 1746–60 | date = May 2011 | pmid = 21542745 | doi = 10.1056/NEJMra1011670 }} 18. ^{{cite web|author=Economist|url=https://www.economist.com/blogs/babbage/2013/11/nanomedicine |title=Nanomedicine: Particle physiology |publisher=The Economist |date=2013-11-05 |accessdate=2013-12-15}} 19. ^{{cite journal | vauthors = Chapman WC, Singla N, Genyk Y, McNeil JW, Renkens KL, Reynolds TC, Murphy A, Weaver FA | title = A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis | journal = Journal of the American College of Surgeons | volume = 205 | issue = 2 | pages = 256–65 | date = August 2007 | pmid = 17660072 | doi = 10.1016/j.jamcollsurg.2007.03.020 }} 20. ^{{cite journal | vauthors = Singla NK, Ballard JL, Moneta G, Randleman CD, Renkens KL, Alexander WA | title = A phase 3b, open-label, single-group immunogenicity and safety study of topical recombinant thrombin in surgical hemostasis | journal = Journal of the American College of Surgeons | volume = 209 | issue = 1 | pages = 68–74 | date = July 2009 | pmid = 19651065 | doi = 10.1016/j.jamcollsurg.2009.03.016 }} 21. ^{{cite journal | vauthors = Greenhalgh DG, Gamelli RL, Collins J, Sood R, Mozingo DW, Gray TE, Alexander WA | title = Recombinant thrombin: safety and immunogenicity in burn wound excision and grafting | journal = Journal of Burn Care & Research | volume = 30 | issue = 3 | pages = 371–9 | year = 2009 | pmid = 19349898 | doi = 10.1097/BCR.0b013e3181a28979 }} 22. ^1 {{cite web|url=http://www.dn.se/nyheter/politik/sverige-rostade-ja-till-kottklister-1.1042136|title=Sverige röstade ja till köttklister|trans-title=Sweden voted in favor of the meat paste|language=Swedish|date=2010-02-09|format=|website=|publisher=Dagens Nyheter|accessdate=2010-10-17}} 23. ^{{cite web|url=https://www.sonac.biz/markets/food-ingredient-supplier/qconnect-fresh-meat-binding/fibrimexr/|title=Welcome to Fibrimex|work=Fibrimex website|publisher=Sonac|accessdate=2019-02-28}} Further reading{{refbegin|2}}
External links
4 : Coagulation system|Acute phase proteins|EC 3.4.21|Peripheral membrane proteins |
| 随便看 |
|
开放百科全书收录14589846条英语、德语、日语等多语种百科知识，基本涵盖了大多数领域的百科知识，是一部内容自由、开放的电子版国际百科全书。